Phosphate-binding polymers for oral administration

ABSTRACT

Phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia.

This is a continuation-in-part of Holmes-Farley et al., U.S. Ser. No.08/105,591, filed Aug. 11, 1993, entitled "Phosphate-Binding Polymersfor Oral Administration", now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to phosphate-binding polymers for oraladministration.

People with inadequate renal function, hypoparathyroidism, or certainother medical conditions often have hyperphosphatemia, meaning serumphosphate levels of over 6 mg/dL. Hyperphosphatemia, especially ifpresent over extended periods of time, leads to severe abnormalities incalcium and phosphorus metabolism, often manifested by aberrantcalcification in joints, lungs, and eyes.

Therapeutic efforts to reduce serum phosphate include dialysis,reduction in dietary phosphate, and oral administration of insolublephosphate binders to reduce gastrointestinal absorption. Dialysis andreduced dietary phosphate are usually insufficient to adequately reversehyperphosphatemia, so the use of phosphate binders is routinely requiredto treat these patients. Phosphate binders include calcium or aluminumsalts, or organic polymers such as ion exchange resins.

Calcium salts have been widely used to bind intestinal phosphate andprevent absorption. The ingested calcium combines with phosphate to forminsoluble calcium phosphate salts such as Ca₃ (PO₄)₂, CaHPO₄, or Ca(H₂PO₄)₂. Different types of calcium salts, including calcium carbonate,acetate (such as the pharmaceutical "PhosLo®"), citrate, alginate, andketoacid salts have been utilized for phosphate binding. The majorproblem with all of these therapeutics is the hypercalcemia which oftenresults from absorption of the high amounts of ingested calcium.Hypercalcemia causes serious side effects such as cardiac arrhythmias,renal failure, and skin and visceral calcification. Frequent monitoringof serum calcium levels is required during therapy with calcium-basedphosphate binders.

Aluminum-based phosphate binders, such as the aluminum hydroxide gel"Amphojel®", have also been used for treating hyperphosphatemia. Thesecompounds complex with intestinal phosphate to form highly insolublealuminum phosphate; the bound phosphate is unavailable for absorption bythe patient. Prolonged use of aluminum gels leads to accumulations ofaluminum, and often to aluminum toxicity, accompanied by such symptomsas encephalopathy, osteomalacia, and myopathy.

Organic polymers that have been used to bind phosphate have typicallybeen ion exchange resins. Those tested include "Dowex®" anion-exchangeresins in the chloride form, such as XF 43311, XY 40013, XF 43254, XY40011, and XY 40012. These resins have several drawbacks for treatmentof hyperphosphatemia, including poor binding efficiency, necessitatinguse of high dosages for significant reduction of absorbed phosphate. Inaddition, the ion exchange resins also bind bile salts.

SUMMARY OF THE INVENTION

In general, the invention features a method of removing phosphate from apatient by ion exchange, which involves oral administration of atherapeutically effective amount of a composition containing at leastone phosphate-binding polymer that is non-toxic and stable onceingested. The polymers of the invention may be crosslinked with acrosslinking agent. Examples of preferred crosslinking agents includeepichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane,1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride,dimethylsuccinate, toluene diisocyanate, acryloyl chloride, andpyromellitic dianhydride. The crosslinking agent is present in an amountranging from about 0.5% to about 75% by weight, more preferably fromabout 2% to about 20% by weight.

By "non-toxic" it is meant that when ingested in therapeuticallyeffective amounts neither the polymers nor any ions released into thebody upon ion exchange are harmful.

By "stable" it is meant that when ingested in therapeutically effectiveamounts the polymers do not dissolve or otherwise decompose to formpotentially harmful by-products, and remain substantially intact so thatthey can transport bound phosphate out of the body.

By "therapeutically effective amount" is meant an amount of thecomposition which, when administered to a patient, causes decreasedserum phosphate.

In one aspect, the polymer is characterized by a repeating unit havingthe formula ##STR1## or a copolymer thereof, wherein n is an integer andeach R, independently, is H or a lower alkyl (e.g., having between 1 and5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino) or aryl (e.g., phenyl)group.

In a second aspect, the polymer is characterized by a repeating unithaving the formula ##STR2## or a copolymer thereof, wherein n is aninteger, each R, independently, is H or a lower alkyl (e.g., havingbetween 1 and 5 carbon atoms, inclusive), alkylamino (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl(e.g., phenyl) group, and each X⁻ is an exchangeable negatively chargedcounterion.

One example of a copolymer according to the second aspect of theinvention is characterized by a first repeating unit having the formula##STR3## wherein n is an integer, each R, independently, is H or a loweralkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino(e.g., having between 1 and 5 carbons atoms, inclusive, such asethylamino) or aryl group (e.g., phenyl), and each X⁻ is an exchangeablenegatively charged counterion; and further characterized by a secondrepeating unit having the formula ##STR4## wherein each n,independently, is an integer and each R, independently, is H or a loweralkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino(e.g., having between 1 and 5 carbons atoms, inclusive, such asethylamino) or aryl group (e.g., phenyl).

In a fourth aspect, the polymer is characterized by a repeating unithaving the formula ##STR5## or a copolymer thereof, wherein n is aninteger, and R is H or a lower alkyl (e.g., having between 1 and 5carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino) or aryl group (e.g.,phenyl).

One example of a copolymer according to the second aspect of theinvention is characterized by a first repeating unit having the formula##STR6## wherein n is an integer, and R is H or a lower alkyl (e.g.,having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g.,having between 1 and 5 carbons atoms, inclusive, such as ethylamino) oraryl group (e.g., phenyl); and further characterized by a secondrepeating unit having the formula ##STR7## wherein each n,independently, is an integer and R is H or a lower alkyl (e.g., havingbetween 1 and 5 carbon atoms, inclusive), alkylamino (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino) or arylgroup (e.g., phenyl).

In a fifth aspect, the polymer is characterized by a repeating grouphaving the formula ##STR8## or a copolymer thereof, wherein n is aninteger, and each R₁ and R₂, independently, is H or a lower alkyl (e.g.,having between 1 and 5 carbon atoms, inclusive), and alkylamino (e.g.,having between 1 and 5 carbons atoms, inclusive, such as ethylamino) oraryl group (e.g., phenyl), and each X⁻ is an exchangeable negativelycharged counterion.

In one preferred polymer according to the fifth aspect of the invention,at least one of the R groups is a hydrogen group.

In a sixth aspect, the polymer is characterized by a repeat unit havingthe formula ##STR9## or a copolymer thereof, where n is an integer, eachR₁ and R₂, independently, is H, an alkyl group containing 1 to 20 carbonatoms, an alkylamino group (e.g., having between 1 and 5 carbons atoms,inclusive, such as ethylamino), or an aryl group containing 1 to 12atoms (e.g., phenyl).

In a seventh aspect, the polymer is characterized by a repeat unithaving the formula ##STR10## or a copolymer thereof, wherein n is aninteger, each R₁, R₂ and R₃, independently, is H, an alkyl groupcontaining 1 to 20 carbon atoms, an alkylamino group (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino), or anaryl group containing 1 to 12 atoms (e.g., phenyl), and each X⁻ is anexchangeable negatively charged counterion.

In all aspects, the negatively charged counterions may be organic ions,inorganic ions, or combination thereof. The inorganic ions suitable foruse in this invention include the halides (especially chloride),phosphate, phosphite, carbonate, bicarbonate, sulfate, bisulfate,hydroxide, nitrate, persulfate, sulfite, and sulfide. Suitable organicions include acetate, ascorbate, benzoate, citrate, dihydrogen citrate,hydrogen citrate, oxalate, succinate, tartrate, taurocholate,glycocholate, and cholate.

The invention provides an effective treatment for decreasing the serumlevel of phosphate by binding phosphate in the gastrointestinal tract,without comcomittantly increasing the absorption of any clinicallyundesirable materials, particularly calcium or aluminum.

Other features and advantages will be apparent from the followingdescription of the preferred embodiments and from the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Preferred polymers have the structures set forth in the Summary of theInvention, above. The polymers are preferably crosslinked, in some casesby adding a crosslinking agent to the reaction mixture duringpolymerization. Examples of suitable crosslinking agents are diacrylatesand dimethacrylates (e.g., ethylene glycol diacrylate, propylene glycoldiacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate,propylene glycol dimethacrylate, butylene glycol dimethacrylate,polyethyleneglycol dimethacrylate, polyethyleneglycol diacrylate),methylene bisacrylamide, methylene bismethacrylamide, ethylenebisacrylamide, epichlorohydrin, toluene diisocyanate,ethylenebismethacrylamide, ethylidene bisacrylamide, divinyl benzene,bisphenol A dimethacrylate, bisphenol A diacrylate, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, acryloylchloride, or pyromellitic dianhydride. The amount of crosslinking agentis typically between about 0.5 and about 75 weight %, and preferablybetween about 1 and about 25% by weight, based upon combined weight ofcrosslinking agent and monomer. In another embodiment, the crosslinkingagent is present between about 2 and about 20% by weight.

In some cases the polymers are crosslinked after polymerization. Onemethod of obtaining such crosslinking involves reaction of the polymerwith difunctional crosslinkers, such as epichlorohydrin, succinyldichloride, the diglycidyl ether of bisphenol A, pyromelliticdianhydride, toluene diisocyanate, and ethylenediamine. A typicalexample is the reaction of poly(ethyleneimine) with epichlorohydrin. Inthis example the epichlorohydrin (1 to 100 parts) is added to a solutioncontaining polyethyleneimine (100 parts) and heated to promote reaction.Other methods of inducing crosslinking on already polymerized materialsinclude, but are not limited to, exposure to ionizing radiation,ultraviolet radiation, electron beams, radicals, and pyrolysis.

EXAMPLES

Candidate polymers were tested by stirring them in a phosphatecontaining solution at pH 7 for 3 h. The solution was designed to mimicthe conditions present in the small intestine.

    ______________________________________           Solution Contents    ______________________________________           10-20 mM Phosphate           80    mM Sodium Chloride           30    mM Sodium Carbonate    ______________________________________

The pH was adjusted to pH 7, once at the start of the test and again atthe end of the test, using either aqueous NaOH or HCl. After 3 h thepolymer was filtered off and the residual phosphate concentration in thetest solution was determined spectrophotometrically. The differencebetween the initial phosphate concentration and the final concentrationwas used to determine the amount of phosphate bound to the polymer. Thisresult is expressed in milliequivalents per gram of starting polymer(meq/g).

The table below shows the results obtained for several polymers. Highernumbers indicate a more effective polymer.

    ______________________________________                              Phosphate                              Bound    Polymer                   (meq/g)*    ______________________________________    Poly(allylamine/epichlorohydrin)                              3.1    Poly(allylamine/butanediol diglycidyl ether)                              2.7    Poly(allylamine/ethanediol diglycidyl ether)                              2.3    Poly(allyltrimethylammonium chloride)                              0.3    Poly(ethyleneimine)/acryloyl chloride                              1.2    Polyethyleneimine "C"     2.7    Polyethyleneimine "A"     2.2    Poly(DET/EPI)             1.5    Polyethyleneimine "B"     1.2    Poly(dimethylaminopropylacrylamide)                              0.8    Poly(PEH/EPI)             0.7    Poly(trimethylammoniomethyl styrene chloride)                              0.7    Poly(pentaethylenehexaminemethacrylamide)                              0.7    Poly(tetraethylenepentaminemethacrylamide)                              0.7    Poly(diethylenetriaminemethacrylamide)                              0.5    Poly(triethylenetetraminemethacrylamide)                              0.5    Poly(aminoethylmethacrylamide)                              0.4    Poly(vinylamine)          0.4    Poly(MAPTAC)              0.25    Poly(methylmethacrylate/PEI)                              0.2    Poly(dimethylethyleneimine chloride)                              0.2    Poly(diethylaminopropylmethacrylamide)                              0.1    Poly(guanidinoacrylamide) 0.1    Poly(guanidinobutylacrylamide)                              0.1    Poly(guanidinobutylmethacrylamide)                              0.1    ______________________________________     *The values apply when the residual solution phosphate levels are ˜     mM.

The table below shows results obtained using various other materials tobind phosphate

    ______________________________________                        Phosphate Bound    Polymer             (meq/g)*    ______________________________________    Calcium Chloride    4.0    Calcium Lactate     2.4    "Ox-Absorb ®"   0.5    "Maalox Plus ®" 0.3    Sephadex DEAE A-25, 40-125 m                        0.2    Aluminum Hydroxide, Dried Gel                        0.2    ______________________________________     *The values apply when the residual solution phosphate levels are ˜     mM.

The table below shows results obtained for a variety of salts made frompolyethyleneimine and organic and inorganic acids.

    ______________________________________                       PHOSPHATE BOUND    POLYMER            (meg/g)*    ______________________________________    Poly(ethyleneimine sulfate A)                       0.9    Poly(ethyleneimine sulfate B)                       1.2    Poly(ethyleneimine sulfate C)                       1.1    Poly(ethyleneimine sulfate D)                       1.7    Poly(ethyleneimine tartrate A)                       0.7    Poly(ethyleneimine tartrate B)                       0.9    Poly(ethyleneimine tartrate C)                       1.1    Poly(ethyleneimine ascorbate A)                       0.55    Poly(ethyleneimine ascorbate B)                       0.65    Poly(ethyleneimine ascorbate C)                       0.9    Poly(ethyleneimine citrate A)                       0.7    Poly(ethyleneimine citrate B)                       1.0    Poly(ethyleneimine citrate C)                       0.9    Poly(ethyleneimine succinate A)                       1.1    Poly(ethyleneimine succinate B)                       1.3    Poly(ethyleneimine chloride)                       1.1    ______________________________________     *The values apply when the residual solution phosphate levels are ˜     mM.

"Oxabsorb®" is an organic polymer that encapsulates calcium such thatthe calcium is available to bind to such ions as phosphate, but may notbe released by the polymer and thus is not supposed to be absorbed bythe patient.

The amount of phosphate bound by all of these materials, both polymersand inorganic gels, is expected to vary as the phosphate concentrationvaries.

In a test, the polymer was exposed to an acidic environment prior toexposure to phosphate as might happen in a patient's stomach. The solid(0.1 g) was suspended in 40 mL of 0.1 M NaCl. This mixture was stirredfor 10 min., and the pH was adjusted to 3.0 with 1 M HCl, and themixture was stirred for 30 min. The mixture was centrifuged, thesupernatant decanted, and the solid resuspended in 40 mL of 0.1 m NaCl.This mixture was stirred for 10 min., the pH was adjusted to 3.0 with 1M HCl, and the mixture was stirred for 30 min. The mixture wascentrifuged, the supernatant decanted, and the solid residue used in theusual phosphate assay. Results are shown below for a variety of polymersand for aluminum hydroxide dried gel. In most cases the values for theamount of phosphate bound are higher in this test than in the usualassay.

    ______________________________________                       PHOSPHATE BOUND    POLYMER            (meg/g)*    ______________________________________    Poly(ethyleneimine sulfate B)                       1.2    Poly(ethyleneimine sulfate C)                       1.3    Poly(ethyleneimine tartrate B)                       1.3    Poly(ethyleneimine tartrate C)                       1.4    Poly(ethyleneimine ascorbate B)                       1.0    Poly(ethyleneimine ascorbate C)                       1.0    Poly(ethyleneimine citrate B)                       1.0    Poly(ethyleneimine citrate C)                       1.3    Poly(ethyleneimine succinate A)                       1.1    Poly(ethyleneimine succinate B)                       1.3    Poly(ethyleneimine chloride)                       1.4    Aluminum Hydroxide 0.7    ______________________________________     *The values apply when the residual solution phosphate levels are ˜     mM.

RAT DIETARY PHOSPHORUS EXCRETION MODEL

Six 6-8 week old Sprague-Dawley rats were placed in metabolic cages andfed semi-purified rodent chow powder containing 0.28% inorganicphosphorus. The diets were supplemented with 11.7%poly(allylamine/epichlorohydrin) or micro-crystalline cellulose; theanimals served as their own controls by receiving cellulose orpoly(allylamine/epichlorohydrin) in randomized order. The rats were fedad libitum for three days to acclimate to the diet. Feces excretedduring the next 48 hours were collected, lyophilized, and ground intopowder. The inorganic phosphate content was determined according to themethod of Taussky and Shorr: Microdetermination of Inorganic P. One gramof powdered feces was burned to remove carbon, then ashed in a 600° C.oven, concentrated HCl was then added to dissolve the phosphorus. Thephosphorus was determined with ferrous sulfate-ammonium molybdatereagent. Intensity of the blue color was determined at 700 nm on aPerkin-Elmer spectrophotometer through a 1 cm cell.

URINARY PHOSPHATE EXCRETION IN PARTIALLY NEPHRECTOMIZED RATS

Sprague-Dawley rats, approximately 8 weeks old, were 75% nephrectomized.One kidney was surgically removed; approximately 50% of the renal arteryflow to the contralateral kidney was ligated. The animals were fed asemi-purified rodent chow containing 0.385% inorganic phosphorus andeither 10% poly(allylamine/epichlorohydrin) or cellulose. Urine wascollected and analyzed for phosphate content on specific days. Absorbeddietary phosphate is excreted into the urine to maintain serumphosphate.

None of the animals became hyperphosphatemic or uremic, indicating thatthe residual kidney function was adequate to filter the absorbedphosphate load. The animals receiving poly(allylamine/epichlorohydrin)demonstrated a trend towards reduced phosphate excretion, indicative ofreduced phosphate absorption.

SYNTHESES

Poly(allylamine) hydrochloride

To a 5 L, water jacketed reaction kettle equipped with 1) a condensertopped with a nitrogen gas inlet and 2) a thermometer and 3) amechanical stirrer was added concentrated hydrochloric acid (2590 mL).The acid was cooled to 5° C. using circulating water in the jacket ofthe reaction kettle at 0° C. Allylamine (2362 mL; 1798 g) was addeddropwise with stirring, maintaining a temperature of 5°-10° C. After theaddition was complete, 1338 mL of liquid was removed by vacuumdistillation at 60°-70° C. Azobis(amidinopropane) dihydrochloride (36 g)suspended in 81 mL water was added. The kettle was heated to 50° C.under a nitrogen atmosphere with stirring for 24 h.Azobis(amidinopropane) dihydrochloride (36 g) suspended in 81 mL waterwas again added and the heating and stirring continued for an addition44 h. Distilled water (720 mL) was added and the solution allowed tocool with stirring. The liquid was added dropwise to a stirring solutionof methanol (30 L). The solid was then removed by filtration,resuspended in methanol (30 L), stirred 1 hour, and collected byfiltration. This methanol rinse was repeated once more and the solid wasdried in a vacuum oven to yield 2691 g of a granular white solid(poly(allylamine) hydrochloride).

Poly(allylamine/epichlorohydrin)

To a 5 gall bucket was added poly(allylamine) hydrochloride (2.5 kg) andwater 10 L). The mixture was stirred to dissolve and the pH was adjustedto 10 with a solid NaOH. The solution was allowed to cool to roomtemperature in the bucket and epichlorohydrin (250 mL) was added all atonce with stirring. The mixture was stirred gently until it gelled afterabout 15 minutes. The gel was allowed to continue curing for 18 h atroom temperature. The gel was then removed and put into a blender withisopropanol (about 7.5 L). The gel was mixed in the blender with about500 mL isopropanol for ˜3 minutes to form coarse particles and the solidwas then collected by filtration. The solid was rinsed three times bysuspended it in 9 gal of water, stirring the mixture for 1 h, andcollecting the solid by filtration. The solid was rinsed once bysuspending it in isopropanol (60 L), stirring the mixture for 1 h, andcollecting the solid by filtration. The solid was dried in a vacuum ovenfor 18 h to yield 1.55 Kg of a granular, brittle, white solid.

Poly(allylamine/butanedioldiglycidyl ether)

To a 5 gallon plastic bucket was added poly(allylamine) hydrochloride(500 g) and water (2 L). The mixture was stirred to dissolve and the pHwas adjusted to 10 with solid NaOH (142.3 g). The solution was allowedto cool to room temperature in the bucket and 1,4-butanedioldiglycidylether (130 mL) was added all at once with stirring. The mixture wasstirred gently until it gelled after 4 minutes. The gel was allowed tocontinue curing for 18 h at room temperature. The gel was then removedand dried in a vacuum oven at 75° C. for 24 h. The dry solid was groundand sieved for -30 mesh and then suspended in 6 gallons on water. Afterstirring for 1 h the solid was filtered off and rinse process repeatedtwice more. The solid was rinsed twice in isopropanol (3 gallons), anddried in a vacuum oven at 50° C. for 24 h to yield 580 g of a whitesolid.

Poly(allylamine/ethanedioldiglycidyl ether)

To a 100 mL beaker was added poly(allylamine) hydrochloride (10 g) andwater (40 mL). The mixture was stirred to dissolve and the pH wasadjusted to 10 with solid NaOH. The solution was allowed to cool to roomtemperature in the beaker and 1,2 ethanedioldiglycidyl ether (2.0 mL)was added all at once with stirring. The mixture was allowed to continuecuring for 18 h at room temperature. The gel was then removed andblended in 500 mL of methanol. The solid was filtered off and suspendedin water (500 mL). After stirring for 1 h the solid was filtered off andthe rising process repeated. The solid was rinsed twice in isopropanol(400 mL), and dried in a vacuum oven at 50° C. for 24 h to yield 8.7 gof a white solid.

Poly(allylamine/dimethylsuccinate)

To a 500 mL round bottom flask was added poly(allylamine) hydrochloride(10 g), methanol (100 mL), and triethylamine (10 mL). The mixture wasstirred and dimethylsuccinate (1 mL) was added. The solution was heatedto reflux and stirring turned off after 30 min. After 18 h the solutionwas cooled to room temperature and solid was filtered off and suspendedin water (1 L). After stirring for 1 h the solid was filtered off andthe rinse process repeated twice more. The solid was rinsed once inisopropanol (800 mL), and dried in a vacuum oven at 50° C. for 24 h toyield 5.9 g of a white solid.

Poly(allyltrimethylammonium chloride)

To a 500 mL three necked flask equipped with a magnetic stirrer, athermometer, and a condenser topped with a nitrogen inlet, was addedpoly(allylamine) crosslinked with epichlorohydrin (5.0 g), methanol (300mL), methyl iodide (20 mL), and sodium carbonate (50 g). The mixture wasthen cooled and water was added to total volume of 2 L. Concentratedhydrochloric acid was added until no further bubbling resulted and theremaining solid was filtered off. The solid was rinsed twice in 10%aqueous NaCl (1 L) by stirring for 1 h followed by filtration to recoverthe solid. The solid was then rinsed three times by suspending it inwater (2 L), stirring for 1 h, and filtering to recover the solid.Finally the solid was rinsed as above in methanol and dried in a vacuumover at 50° C. for 18 h to yield 7.7 g of white granular solid.

Poly(ethyleneimine)/acryloyl chloride

Into a 5 L three neck flask equipped with a mechanical stirrer, athermometer, and an additional funnel was added polyethyleneimine (510 gof a 50% aqueous solution (equivalent to 255 g of dry polymer) andisopropanol (2.5 L). Acryloyl chloride (50 g) was added dropwise throughthe addition funnel over a 35 minute period, keeping the temperaturebelow 29° C. The solution was then heated to 60° C. with stirring for 18h. The solution was cooled and solid immediately filtered off. The solidwas rinsed three times by suspending it in water (2 gallons), stirringfor 1 h, and filtering to recover the solid. The solid was rinsed onceby suspending it in methanol (2 gallons), stirring for 30 minutes, andfiltering to recover the solid. Finally, the solid was rinsed as abovein isopropanol and dried in a vacuum over at 50° C. for 18 h to yield206 g of light orange granular solid. ##STR11##

Poly(dimethylaminopropylacrylamide)

Dimethylaminopropylacrylamide (10 g) and methylenebisacrylamide (1.1 g)were dissolved in 50 mL of water in a 100 mL three neck flask. Thesolution was stirred under nitrogen for 10 minutes. Potassium persulfate(0.3 g) and sodium metabisulfite (0.3 g) were each dissolved in 2-3 mLof water and then mixed. After a few seconds this solution was added tothe monomer solution, still under nitrogen. A gel formed immediately andwas allowed to sit overnight. The gel was removed and blended with 500mL of isopropanol. The solid was filtered off and rinsed three timeswith acetone. The solid white powder was filtered off and dried in avacuum oven to yield 6.1 g. ##STR12##

Poly(Methacrylamidopropyltrimethylammoniumchloride)=[Poly(MAPTAC)]

[3-(Methacryloylamino)propyl]trimethylammonium chloride (38 mL of 50%aqueous solution) and methylenebismethacrylamide (2.2 g) were stirred ina beaker at room temperature. Methanol (10 mL was added and the solutionwas warmed to 40° C. to fully dissolve the bisacrylamide. Potassiumpersulfate (0.4 g) was added and the solution stirred for 2 min.Potassium metabisulfite (0.4 g) was added and stirring was continued.After 5 min the solution was put under a nitrogen atmosphere. After 20min the solution contained significant precipitate and the solution wasallowed to sit overnight. The solid was washed three times withisopropanol and collected by filtration. The solid was then suspended inwater 500 (mL) and stirred for several hours before being collected bycentrifugation. The solid was again washed with water and collected byfiltration. The solid was then dried in a vacuum oven to yield 21.96 g.##STR13##

Poly(ethyleneimine) "A"

Polyethyleneimine (50g of a 50% aqueous solution; Scientific PolymerProducts) was dissolved in water (100 mL). Epichlorohydrin (4.6 mL) wasadded dropwise. The solution was heated to 55° C. for 4 h, after whichit had gelled. The gel was removed, blended with water (1 L) and thesolid was filtered off. It was resuspended in water (2 L) and stirredfor 10 min. The solid was filtered off, the rinse repeated once withwater and twice with isopropanol, and the resulting gel was dried in avacuum oven to yield 26.3 g of a rubbery solid.

Poly(ethyleneimine) "B" and Poly(ethyleneimine)"C", were made in asimilar manner, except using 9.2 and 2.3 mL of epichlorohydrin,respectively.

Poly(methylmethacrylate-co-divinylbenzene)

Methylmethacrylate (50 g) and divinylbenzene (5 g) andazobisisobutyronitrile (1.0 g) were dissolved in isopropanol (500 mL)and heated to reflux for 18 h under a nitrogen atmosphere. The solidwhite precipitate was filtered off, rinsed once in acetone (collected bycentrifugation), once in water (collected by filtration) and dried in avacuum oven to yield 19.4 g. ##STR14##Poly(diethylenetriaminemethacrylamide)

Poly(methylmethacrylateocodivinylbenzene) (20 g) was suspended indiethylenetriamine (200 mL) and heated to reflux under a nitrogenatmosphere for 18 h. The solid was collected by filtration, resuspendedin water (500 mL), stirred 30 min, filtered off, resuspended in water(500 mL), stirred 30 min, filtered off, rinsed briefly in isopropanol,and dried in a vacuum oven to yield 18.0 g. ##STR15##

Poly(pentaethylenehexaminemethacrylamidel,Poly(tetraethylenepentaminemethacrylamide), andpoly(triethylenetetraaminemethacrylamide) were made in a manner similarto poly(diethylenetriaminemethacrylamide) from pentaethylenehexamine,tetraethylenepentamine, and triethylenetetraamine, respectively.

Poly(methylmethacrylate/PE1)

Poly(methylmethacrylate-co-divinylbenzene) (1.0 g) was added to amixture containing hexanol (150 mL) and polyethyleneimine (15 g in 15 gwater). The mixture was heated to reflux under nitrogen for 4 days. Thereaction was cooled and the solid was filtered off, suspended inmethanol (300 mL), stirred 1 h, and filtered off. The rinse was repeatedonce with isopropanol and the solid was dried in a vacuum oven to yield0.71 g. ##STR16##

Poly(aminoethylmethacrylamide)

Poly(methylmethacrylate-co-divinylbenzene) (20 g) was suspended inethylenediamine (200 mL) and heated to reflux under a nitrogenatmosphere for 3 days. The solid was collected by centrifugation, washedby resuspending it in water (500 mL), stirring for 30 min, and filteringoff the solid. The solid was washed twice more in water, once inisopropanol, and dried in a vacuum oven to yield 17.3. g. ##STR17##

Poly(diethylaminopropylmethacrylamide)

Poly(methylmethacrylate-co-divinylbenzene) (20 g) was suspended indiethylaminopropylamine (200 mL) and heated to reflux under a nitrogenatmosphere for 18 h. The solid was collected by filtration, resuspendedin water (500 mL), filtered off, resuspended in water (500 mL),collected by filtration, rinsed briefly in isopropanol, and dried in avacuum oven to yield 8.2 g. ##STR18##

NHS-acrylate

N-Hydroxysuccinimide (NHS, 157.5 g) was dissolved in chloroform (2300mL) in a 5 L flask. The solution was cooled to 0° C. and acryloylchloride (132 g) was added dropwise, keeping the temperature <2° C.After addition was complete, the solution was stirred for 1.5 h, rinsedwith water (1100 mL) in a separatory funnel and dried over anhydroussodium sulfate. The solvent was removed under vacuum and a small amountof ethyl acetate was added to the residue. This mixture was poured intohexane (200 mL) with stirring. The solution was heated to reflux, addingmore ethyl acetate (400 mL). The insoluble NHS was filtered off, hexane(1 L) was added, the solution was heated to reflux, ethyl acetate (400mL) was added, and the solution allowed to cool to <10° C. The solid wasthen filtered off and dried in a vacuum oven to yield 125.9 g. A secondcrop of 80 g was subsequently collected by further cooling. ##STR19##

Poly(NHS-acrylate)

NHS-acrylate (28.5 g), methylenebisacrylamide (1.5 g) andtetrahydrofuran (500 mL) were mixed in a 1 L flask and heated to 50° C.under a nitrogen atmosphere. Azobisisobutyronitrile (0.2 g) was added,the solution was stirred for 1 h, filtered to remove excessN-hydroxysuccinimide, and heated to 50° C. for 4.5 h under a nitrogenatmosphere. The solution was then cooled and the solid was filtered off,rinsed in tetrahydrofuran, and dried in a vacuum oven to yield 16.1 g.##STR20##

Poly(guanidinobutylacrylamide)

Poly(NHS-acrylate) (1.5 g) was suspended in water (25 mL) containingagmatine (1.5 g) which had been adjusted to pH 9 with solid NaOH. Thesolution was stirred for 4 days, after which time the pH had dropped to6.3. Water was added to a total of 500 mL, the solution was stirred for30 min, and the solid was filtered off. The solid was rinsed twice inwater, twice in isopropanol, and dried in a vacuum oven to yield 0.45 g.##STR21##

Poly(methacryloyl chloride)

Methacryloyl chloride (20 mL), divinyl benzene (4 mL of 80% purity),AIBN (0.4 g), and THF (150 mL) were stirred at 60° C. under a nitrogenatmosphere for 18 h. The solution was cooled and the solid was filteredoff, rinsed in THF, then acetone, and dried in a vacuum oven to yield8.1 g. ##STR22##

Poly(guanidinobutylmethacrylamide)

Poly(methacryloyl chloride) (0.5 g), agmatine sulfate (1.0 g),triethylamine (2.5 mL), and acetone (50 mL) were stirred together for 4days. Water (100 mL) was added and the mixture stirred for 6 h. Thesolid was filtered off and washed by resuspending in water (500 mL),stirring for 30 min, and filtering off the solid. The wash was repeatedtwice in water, once in methanol, and the solid was dried in a vacuumoven to yield 0.41 g. ##STR23##

Poly(guanidinoacrylamide)

The procedure for poly(guanidinobutylacrylamide) was followedsubstituting aminoguanidine bicarbonate (5.0 g) for the agmatine,yielding 0.75 g.

Poly(PEH/EPI)

Epichlorohydrin (21.5 g) was added dropwise to a solution containingpentaethylenehexamine (20 g) and water (100 mL), keeping the temperaturebelow 65° C. The solution was stirred until it gelled and heating wascontinued for 4 h (at 65° C.). After sitting overnight at roomtemperature the gel was removed and blended with water (1 L). The solidwas filtered off, water was added (1 L), and the blending and filtrationwere repeated. The gel was suspended in isopropanol and the resultingsolid was collected by filtration and dried in a vacuum oven to yield28.2 g. ##STR24## Ethylidenebisacetamide

Acetamide (118 g), acetaldehyde (44.06 g), copper acetate (0.2 g), andwater (300 mL) were placed in a 1 L three neck flask fitted withcondenser, thermometer, and mechanical stirrer. Concentrated HCl (34 mL)was added and the mixture was heated to 45°-50° C. with stirring for 24h. The water was then removed in vacuo to leave a thick sludge whichformed crystals on cooling to 5° C. Acetone (200 mL) was added andstirred for a few minutes after which the solid was filtered off anddiscarded. The acetone was cooled to 0° C. and solid was filtered off.This solid was rinsed in 500 mL acetone and air dried 18 h to yield 31.5g. ##STR25## Vinylacetamide

Ethylidenebisacetamide (31.05 g), calcium carbonate (2 g) and celite 541(2 g) were placed in a 500 mL three neck flask fitted with athermometer, a mechanical stirrer, and a distilling head atop a vigrouxcolumn. The mixture was vacuum distilled at 35 mm Hg by heating the potto 180°-225° C. Only a single fraction was collected (10.8 g) whichcontained a large portion of acetamide in addition to the product(determined by NMR). This solid product was dissolved in isopropanol (30mL) to form the crude solution used for polymerization. ##STR26##Poly(vinylacetamide)

Crude vinylacetamide solution (15 mL), divinylbenzene (1 g, technicalgrade, 55% pure, mixed isomers), and AIBN (0.3g) were mixed and heatedto reflux under a nitrogen atmosphere for 90 min, forming a solidprecipitate. The solution was cooled, isopropanol (50 mL) was added, andthe solid was collected by centrifugation. The solid was rinsed twice inisopropanol, once in water, and dried in a vacuum oven to yield 0.8 g.##STR27## Poly(vinylamine)

Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one neck flaskcontaining water 25 mL and concentrated HCl 25 mL. The mixture wasrefluxed for 5 days, the solid was filtered off, rinsed once in water,twice in isopropanol, and dried in a vacuum oven to yield 0.77g. Theproduct of this reaction (˜0.84 g) was suspended in NaOH (46 g) andwater (46 g) and heated to boiling (˜140° C). Due to foaming thetemperature was reduced and maintained at ˜100° C. for 2 h. Water (100mL) was added and the solid collected by filtration. After rinsing oncein water the solid was suspended in water (500 mL) and adjusted to pH 5with acetic acid. The solid was again filtered off, rinsed with water,then the isopropanol, and dried in a vacuum oven to yield 0.51 g.

Poly(trimethylammoniomethylstyrene chloride) is the copolymer oftrimethylammoniomethylstyrene chloride and divinyl benzene.

Poly(DET/EPI) is the polymer formed by reaction of diethylenetriamineand epichlorohydrin.

Poly(ethyleneimine) Salts

Polyethyleneimine (25 g dissolved in 25 g water) was dissolved in water(100 mL) and mixed with toluene (1 L). Epichlorohydrin (2.3 mL) wasadded and the mixture heated to 60° C. with vigorous mechanical stirringfor 18 h. The mixture was cooled and the solid filtered off, resuspendedin methanol (2 L), stirred 1 h, and collected by centrifugation. Thesolid was suspended in water (2 L), stirred 1 h, filtered off, suspendedin water (4 L), stirred 1 h, and again filtered off. The solid wassuspended in acetone (4 L) and stirred 15 min., the liquid was pouredoff, acetone (2 L) was added, the mixture was stirred 15 min., theacetone was again poured off, and the solid was dried in a vacuum ovento form intermediate "D".

Poly(ethyleneimine sulfate A)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with sulfuric acid (1.1 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine sulfate B)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with sulfuric acid (0.57 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine sulfate C)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with sulfuric acid (0.28 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine sulfate D)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with sulfuric acid (0.11 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine tartrate A)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min, and partially neutralized with tartaric acid (1.72 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine tartrate B)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with tartaric acid (0.86 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine tartrate C)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with tartaric acid (0.43 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine ascorbate A)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with ascorbic acid (4.05 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine ascorbate B)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with ascorbic acid (2.02 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine ascorbate C)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min., and partially neutralized with ascorbic acid (1.01 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine citrate A)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min, and partially neutralized with citric acid (1.47 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine citrate B)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min, and partially neutralized with citric acid (0.74 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine citrate C)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min, and partially neutralized with citric acid (0.37 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine succinate A)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min, and partially neutralized with succinic acid (1.36 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine succinate B)

Intermediate "D" (1.0 g) was suspended in water (150 mL), stirred 30min, and partially neutralized with succinic acid (0.68 g). The mixturewas stirred an additional 30 minutes, the solid was filtered off,resuspended in methanol (200 mL), stirred 5 min., filtered off, anddried in a vacuum oven.

Poly(ethyleneimine chloride)

Polyethyleneimine (100 g in 100 g water) was dissolved in water (640 mLadditional) and the pH was adjusted to 10 with concentrated HCl.Isopropanol (1.6 L) was added, followed by epichlorohydrin (19.2 mL).The mixture was stirred under nitrogen for 18 h at 60° C. The solidswere filtered off and rinsed with methanol (300 mL) on the funnel. Thesolid was rinsed by resuspending it in methanol (4 L), stirring 30 min.,and filtering off the solid. The rinse was repeated twice with methanol,followed by resuspension in water (1 gallon). The pH was adjusted to 1.0with concentrated HCl, the solid was filtered off, resuspended in water(1 gallon), the pH again adjusted to 1.0 with concentrated HCl, themixture stirred 30 min., and the solid filtered off. The methanol rinsewas again repeated and the solid dried in a vacuum oven to yield 112.4g.

Poly(dimethylethyleneimine chloride)

Poly(ethyleneimine chloride) (5.0 g) was suspended in methanol (300 mL)and sodium carbonate (50 g) was added. Methyl iodide (20 mL) was addedand the mixture heated to reflux for 3 days. Water was added to reach atotal volume of 500 mL, the mixture stirred for 15 min., and the solidfiltered off. The solid was suspended in water (500 mL), stirred 30minutes, and filtered. The solid was suspended in water (1 L), the pHadjusted to 7.0 with concentrated HCl, and the mixture stirred for 10min. The solid was filtered off, resuspended in isopropanol (1L),stirred 30 min., filtered off, and dried in a vacuum oven to yield 6.33g.

Use

The methods of the invention involve treatment of patients withhyperphosphatemia. Elevated serum phosphate is commonly present inpatients with renal insufficiency, hypoparathyroidism,pseudohypoparathyroidism, acute untreated acromegaly, overmedicationwith phosphate salts, and acute tissue destruction as occurs duringrhabdomyolysis and treatment of malignancies.

The term "patient" used herein is taken to mean any mammalian patient towhich phosphate binders may be administered. Patients specificallyintended for treatment with the methods of the invention include humans,as well as nonhuman primates, sheep, horses, cattle, goats, pigs, dogs,cats, rabbits, guinea pigs, hamsters, gerbils, rats and mice.

The compositions utilized in the methods of the inventions are orallyadministered in therapeutically effective amounts. A therapeuticallyeffective amount of compound is that amount which produces a result orexerts an influence on the particular condition being treated. As usedherein, a therapeutically effective amount of a phosphate binder meansan amount which is effective in decreasing the serum phosphate levels ofthe patient to which it is administered.

The present pharmaceutical compositions are prepared by known proceduresusing well known and readily available ingredients. In making thecompositions of the present invention, the polymeric phosphate bindermay be present alone, may be admixed with a carrier, diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the polymer. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, syrups, aerosols, (as a solid or in aliquid medium), soft or hard gelatin capsules, sterile packaged powders,and the like. Examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methylhydroxybenzoates, propylhydroxybenzoates,propylhydroxybenzoates, and talc.

It should be understood, however, that the foregoing description of theinvention is intended merely to be illustrative by way of example onlyand that other modifications, embodiments, and equivalents may beapparent to those skilled in the art without departing from its spirit.

What is claimed is:
 1. A method for removing phosphate from a patient byion exchange comprising orally administering to said patient atherapeutically effective amount of a composition comprising at leastone polymer characterized by a repeat unit having the formula ##STR28##or a copolymer thereof, wherein n is an integer and each R,independently, is H or a lower alkyl, alkylamino, or aryl group.
 2. Themethod of claim 1 wherein said polymer is crosslinked with acrosslinking agent wherein said crosslinking agent is present in saidcomposition from about 0.5% to about 75% by weight.
 3. The method ofclaim 2 wherein said crosslinking agent comprises epichlorohydrin, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluenediisocyanate, acryloyl chloride, or pyromellitic dianhydride.
 4. Themethod of claim 3 wherein said crosslinking agent comprisesepichlorohydrin.
 5. The method of claim 2 wherein said crosslinkingagent is present in said composition from about 2% to about 20% byweight.
 6. A method for removing phosphate from a patient by ionexchange comprising orally administering to said patient atherapeutically effective amount of a composition comprising at leastone polymer characterized by a repeat unit having the formula ##STR29##or a copolymer thereof, wherein each n is an integer, each R,independently, is H or a lower alkyl, alkylamino, or aryl group, andeach X⁻ is an exchangeable negatively charged counterion.
 7. The methodof claim 6 wherein said polymer is crosslinked with a crosslinking agentwherein said crosslinking agent is present in said composition fromabout 0.5% to about 75% by weight.
 8. The method of claim 7 wherein saidcrosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidylether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane,1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyldichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride,or pyromellitic dianhydride.
 9. The method of claim 7 wherein saidcrosslinking agent is present in said composition from about 2% to about20% by weight.
 10. The method of claim 6 wherein the polymer is acopolymer comprising a second repeat unit having the formula ##STR30##wherein each n, independently, is an integer and each R, independently,is H or a lower alkyl, alkylamino, or aryl group.
 11. The method ofclaim 10 wherein said polymer is crosslinked with a crosslinking agentwherein said crosslinking agent is present in said composition fromabout 0.5% to about 75% by weight.
 12. The method of claim 11 whereinsaid crosslinking agent comprises epichlorohydrin, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluenediisocyanate, acryloyl chloride, or pyromellitic dianhydride.
 13. Themethod of claim 11 wherein said crosslinking agent is present in saidcomposition from about 2% to about 20% by weight.
 14. A therapeuticcomposition for removing phosphate from a patient by ion exchangecomprising a therapeutically effective amount of at least one polymercharacterized by a repeat unit having the formula ##STR31## or copolymerthereof, wherein n is an integer and each R, independently, is H or alower alkyl, alkylamino, or aryl group.
 15. The composition of claim 14wherein said polymer is crosslinked with a crosslinking agent whereinsaid crosslinking agent is present in said composition from about 0.5%to about 75% by weight.
 16. The composition of claim 15 wherein saidcrosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidylether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane,1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyldichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride,or pyromellitic dianhydride.
 17. The composition of claim 16 whereinsaid crosslinking agent comprises epichlorohydrin.
 18. The compositionof claim 15 wherein said crosslinking agent is present in saidcomposition from about 2% to about 20% by weight.